1. Field of the Invention
The present invention relates to the fields of molecular biology and oncology. More specifically, it deals with the identification of a molecular interaction between the product of the c-myc oncogene and p19Arf. The present invention also provides for methods of identifying agents that alter this interaction.
2. Description of Related Art
Numerous studies have demonstrated an essential role for the c-myc gene in the control of cell proliferation. Deregulated c-myc expression has been demonstrated in many types of human cancer, including Burkitt's lymphoma, myeloid and plasma cell leukemia, breast carcinoma, cervical carcinoma, small cell lung carcinoma, colon carcinoma, osteosarcoma, and glioblastoma (Oster et al., 2002; Spencer and Groudine, 1991). Overexpression studies illustrate the diverse biological activities of c-myc, including the ability to stimulate cellular proliferation, cause cellular immortalization, inhibit terminal differentiation (Henriksson and Luscher, 1996; Lemaitre et al., 1996), induce apoptosis in cells deprived of survival factors (Askew et al., 1991; Bissonnette et al., 1994), contribute to genomic instability and chromosomal alterations (Felsher and Bishop, 1999; Li and Dang, 1999), transform cells in vitro, and cause tumorigenesis (Facchini and Penn, 1998; Henriksson and Luscher, 1996).
The c-Myc protein is a transcription factor that has been shown to both upregulate and downregulate a variety of target genes. Heterodimerization with its protein partner, Max, is required for sequence-specific DNA binding to a specific E box element as well as for biological activity (Oster et al., 2002). Transactivation of target gene promoters by c-Myc also requires binding of factors to the amino-terminal transactivation domain, such as TRRAP and Tip48/49 (Oster et al., 2002). c-Myc upregulates several proliferative genes, such as cyclin D, cyclin E, and cdk4 (Oster et al., 2002). Also, antiproliferative genes, such as cyclin-dependent kinase inhibitors (CDK-I) p21Cip1, p15Ink4b, p27Kip1, and several of the gadd genes, can be repressed by c-Myc to facilitate cell cycle progression (Oster et al., 2002). The tumor suppressor, p19ARF (ARF), which is induced by c-Myc, Ras and E2F, mediates p53 activation by sequestering Mdm2 and thus inhibiting the Mdm2-dependent degradation of p53 (Bates et al., 1998; Pomerantz et al., 1998; Zhang et al., 1998; Zindy et al., 1998). Inactivation of the ARF-Mdm2-p53 pathway allows oncogenic c-Myc to drive cell cycle progression without apoptosis (Eischen et al., 1999). Unchecked cell cycle progression leads to transformation and tumorigenesis, as illustrated by the observation that mice lacking ARF are highly prone to tumor development (Haviernik et al., 2003; Kamijo et al., 1999).